2, 4-dibromo-9-halo-allopregnanes



United States Patent 3,133,093 2,d-DEBRCMC-9-HALO-ALLPREGNANES Lewis H. Sarett, Princeton, NJ assignor to Merck & Co., Inc, Rahway, Ni, a corporation of New Jersey No Drawing. Continuation of application Ser. No. 511,404, May 26, 1955. This appiication June 21,

1961, Ser. No. 118,494

8 Ciaims. (Ci. 260-39745) This invention is concerned generally with novel steroid compounds and processes of preparing them. More particularly, it relates to 9-halo derivatives of A -3,20-diketo 17 hydroxy 11,21 bisoxygenated-pregnadiene compounds, and to processes of preparing these compounds starting with 9-halo cortisone and 9-halo hydrocortisone. These novel 9-halo-A -3,20-diketo-17-hydroxy 11,21 bis-oXygenated-pregnadiene compounds (hereinafter sometimes referred to in this application as 9-halo-retrocortin compounds) possess cortisone activity, but differ from cortisone and hydrocortisone in not possessing sodium or water retention action. These novel 9-halo derivatives of A -3,20-diketo-17-hydr0Xy-1 1,21- bis-oxygenated-pregnadiene compounds are especially eifective in the treatment of arthritis and related diseases since they can be administered for their cortisone action Without producing the undesired metabolic effects such as edema, which are caused by the sodium and water retention action of cortisone.

This application is a continuation of application Serial No. 511,404, filed on May 26, 1955, now abandoned which is in turn a continuation-in-part of applications Serial Nos. 481,955, now abandoned; 481,956, now US. Patent No. 2,736,734 and 481,957, now US. Patent No. 2,789,117, all filed on January 14, 1955.

These novel 9-halo derivatives of A -3,20-diketo-17- hydroxy 11,21 bis-oxygenated-pregnadiene compounds, subiect of the present invention, may be chemically represented as follows:

CHzOR wherein R is hydrogen or an acyl radical, Z is a keto or hydroxy radical, and Y is a halogen substituent.

These 9 halo A 3,20 diketo 17 hydroxy 11, 21-bis-oxygenated-pregnadiene compounds can be prepared by reacting a 9-halo-3,20-diketo-11-oxygenated-17- hydroxy-Zl-acyloxy-allopregnane compound (Compound 1 hereinbelow) with approximately 2 molecular equivalents of bromine to form the corresponding 2,4-dibromo- 9 halo 3,20 diketo 11 oxygenated 17 hydroxy- 21-acy1oxy-allo-pregnane (Compound 2); the latter compound is reacted with a dehydrohalogenating agent to produce a 9-halo-A -3,20-diketo-1l-oxygenated-17-hydr0xy-2l-acyloxy-pregnadiene (Compound 3) which upon reaction with a hydrolyzing agent is converted to the corresponding 9 halo A 3,20 diketo 11 oxygenated 17,21-dihydroXy-pregnadiene (Compound 4). The

3,133,993 Patented May 12, 1964 ice reactions indicated hereinabove may be chemically represented as follows:

Compound 3 wherein R is acyl, and Z and Y have the significance above-defined.

The 9 halo 3,20 diketo 11 oxygenated 17 hydroxy-Zl-acyloxy-allopregnane compounds used as starting materials in the foregoing procedure include 9-halo- 3,11,20 triketo 17 hydroxy 21 acyloxy allopregnane compounds as for example 9a-chloro-3,11,20-triketo 17m hydroxy 21 acyloxy allopregnanes, such as chloro 3,11,20 triketo :,21 dihydroxyallopregnane 21-acetate, 9u-ohloro-3,11,20-triketo-17a, 2l-dihydroxy-allopregnane 21-propionate, 9oc-fl110I0-3,11, 20 triketo 17a hydroxy 21 acyloxy allopregnanes such as 9m-fluoro-3,l1,20-triketo-17u,21-dihydroxy-a11opregnane ZI-acetate, 9a-fluoro-3,11,20-triketo-17a,21-dihydroxy-allopregnane 21-propionate, 9'a-fll10I'0-3,11,20- triketo 17oc,21 dihydroxy allopregnane 21 (tertiary butyl-acetate), 90c fluoro 3,11,20 triketo 17a,21- dihydroxy-allopregnane 21-phosphate, 9-halo-3,20-diketo- 11,17-dihydroxy-2l-acyloxy-allopregnane compounds as for example 9a-chloro-3,20-diketo-11B,17a-dihydroxy-21- acyloxy-allopregnanes such as 9a-chloro-3,20-diketo-115, 17a,21 trihydroxy allopregnan e 21 acetate, 90C-Ch101'0- 3,20 diketo 11B,17oc,21 trihydroXy-allopregnane 21- propionate, 9a fluoro 3,20 diketo 1113,1704 dihydroxy-Zl-acyloxy-allopregnanes such as 9a-fluoro-3,20-diketo 11/3,17oc,21 trihydroxy allopregnane 21 acetate, 91x fluoro 3,20 diketo l1fi3,17cc,2l trihydroxyallopregnane 21-propionate, 9a-fluoro-3,20-diketo-11,6, 17a,21 trihydroxy-allopregnane 21 (tertiary butyl-acetate), 90c fluoro 3,20 diketo 11B,17a,21 trihyd'roxyallopregnane 21-phosphate, and the like.

These 9 halo 3,11,20 triketo 17 hydroxy 21- acyloxy-allopregnanes and 9-halo-3,20-diketo-11,17-dihydroxy-2l-acyloxy-allopregnanes are conveniently prepared by reacting the corresponding esters of cortisone and hydrocortisone, i.e. 9a-halo-A -3,l1,20-triketo-17ahydroxy-2l-acyloxy-pregnene and 9a-halo-A -3,20-diketo- 11,8,170; dihydroxy 21 acyloxy-pregnene, with hydrogen in the presence of a palladium catalyst whereby the double bond connecting the C-4 and C-5 carbon atoms is hydrogenated to produce the corresponding allopregnane compounds without substantially alfecting other reducible bonds in the molecule.

The bromination reaction is ordinarily carried out, in accordance with the present invention, by dissolving the 9-halo-3,20-diket0 11 oxygenated-17-hydroxy-2lacyloxy-allopregnane compound in a solvent inert to bromine, as for example a halogenated hydrocarbon such as chloroform, carbon tetrachloride, glacial acetic acid, and the like, and adding the bromine to the resulting solution. It is preferred to conduct the brornination at room temperature by adding a solution of bromine in chloroform or glacial acetic acid, dropwise, to a solution of the 9-halo-3,20-diketo-11-oxygenated-17-hydroxy-2lacyloxy-allopregnane in chloroform containing a small amount of hydrogen bromide. The product is conveniently recovered from the bromination mixture by evaporating the solvent; the residual material may be purified, if desired, by recrystallization from a solvent such as ethyl acetate to give the 2,4-dibromo-9-halo-3,20-diketo- 11-oxygenated-17-hydroxy-2l-acyloxy-allopregnane compounds as for example 2,4-dibromo-9-halo-3,l1,2(l-triketo-17-hydroxy-2l-acyloxyallopregnanes such as 2,4-dibromo-9a-chloro-3,1 1,ZO-triketo-17a-hydroxy-21- acyloxy-allopregnane, 2,4-dibrorno-9a-chloro-3,1l,20-triketo-17a,2l-dihydroxyallopregnane 2l-acetate, 2,4-dibromo-9 a-chloro-3 ,1 1,20-triketo-17a,21-dihydroxyallopregnane 21-propionate, 2,4-dibromo-9 a-fluoro-3,1 1,20-triketo-17a-hydroxy-21- acyloxy-allopregnane, 2,4-dibromo-9ot-fluoro-3,1 1,20-triketo-17a,21-dihydroxyallopregnane 2l-acetate, 2,4-dibromo-9a-fluoro-3,l1,20-triketo-17a,21-dihydroxyallopregnane 21-propionate, 2,4-dibromo-9ot-fluoro-3, 1 1,20-triketo-17a,21-dihydroxyallopregnane 21-(tertiary butyl-acetate), 2.,4-dibromo-9u-fluoro-3 ,1 1,20-triketo- 17a,21-dihydroxyallopregnane 21-phosphate, 2,4-dibromo-9-halo-3,ZO-diketo 11,17 dihydroxy 21- acyloxy-allopregnanes such as 2,4-dibromo-9a-chloro-3,20-diketo-1 15, l7tx-dihydroxy- 21-acyloxy-allopregnane, 2,4-dibromo-9a-chloro-3,ZO-diketo-l 1B,17u,2l-trihydroxy-allopregnane 21-acetate, 2,4-dibromo-9a-chloro-3,20-diketo-1 1,B,17u,21-trihydroxy-allopregnane 2l-propionate, 2,4-dibromo-9 m-fluoro-3 ,ZO-diketo-l 1,8,17u-dihydroxy 2l-acyloxy-allopregnane, 2,4-dibromo-9a-fluoro-3 ,ZO-diketo-l 1fi,17a,2l-trihydroxy-allopregnane 2l-acetate, 2,4-dibromo-9a-fluoro-3,20-dilreto-1 1 {3, 1 7a,2l-trihydroxy-allopregnane 21-propionate, 2,4-dibromo-9a-fluoro-3,20-diketo-11fi,17a,2l-trihydroxy-allopregnane 21- (tertiary butyl-acetate), 2,4-dibromo-9a-fiuoro-3,ZO-diketo-l l,8,17u,21-trihydroxy-allopregnane 21-phosphate, and the like.

The dehydrohalogenation of the 2,4-dibrorno-9-halo-3, 20diketo-11-oxygenated 17 hydroxy-Zl-acyloxy-allopregnane compound thus formed can be carried out by reacting the 2,4-dibromo compound with a tertiary amine such as pyridine, collidine, and the like. If desired, a nitrogenous ketone reagent such as 2,4-dinitrophenylhydrazine, semicarbazide, and the like, can be utilized as the dehydrohalogenating agent. When a tertiary amine is utilized as the dehydrohalogenating agent, the reaction is conveniently conducted by heating the reactants (the 2,4-dibromo-9-halo 3,20 a diketo 11 oxygenated-17 hydroxy-Zl-acyloxy-allopregnane and the tertiary amine) under reflux for a period of about one hour, thereby forming the corresponding 9-halo-A -3,2O-diketo-11- oxygenated-l7-hydroxy 21 acyloxy-pregnadiene compound. This product is conveniently recovered from the reaction mixture by cooling the mixture and pouring it into ice Water whereupon the 9-halo-A -3,2O-diketo11- oxygenated-17-hydroxy 21 acyloxy-pregnadiene ordinarily precipitates and is recovered by filtration. In the case of the phosphate esters (i.e. the 9-halo-A -3,20- diketo 11 oxygenated 17,21 dihydroxy pregnadiene 2l-phosphates) which are relatively soluble in Water, the dilution of the reaction mixture with water gives an aqueous solution which is first contacted with an excess of a sulfonic type cation exchange resin on the hydrogen cycle (thereby adsorbing the tertiary amine from the solution) and then contacted with an anion-exchange resin to adsorb bromide ion. Evaporation of the resulting aqueous solution to dryness gives the desired 9-halo- A -3,20-diketo-1l-oxygenated 17,21 dihydroxy-pregnadiene 2l-phosphate.

When a nitrogenous ketone reagent (such as 2,4-dinitrophenylhydrazine or semicarbazide) is employed for the 2,4-dibromo-9-halo-3,ZO-diketo-l1-oxygenated-l7-hydroxy-2l-acyloxy-allopregnane is preferably brought into contact with the 2,4-dinitrophenylhydrazine or semicarbazide reagent in a medium comprising glacial acetic acid, at a temperature of about 5055 C., thereby forming the intermediate 3-(2,4-dinitrophenylhydrazone) or 3-semicarbazone of the 9-halo-A -3,20'-diketo-ll-oxygenated-17-hydroxy-21-acyloxy-pregnadiene; the glacial acetic acid reaction mixture is then diluted with water and cooled, whereupon the 3-(2,4-dinitrophenylhydrazone) or 3-semicarbazone precipitates, and is recovered by filtration and dried. The 3-(2,4-dinitr0phenylhydrazone) or 3-semicarbazone is hydrolyzed, without further purification, by heating, in glacial acetic acid solution in the presence of a carbonyl acceptor such as pyruvic acid, at an elevated temperature of approximately -85 (3., thereby forming the corresponding 9-halo-A -3,20-diketo 11 oxygenated 17 hydroxy-2l-acyloxy-pregnadiene compound.

The 9-halo-A -3,20-diketo-11-oxygenated-17-hydroxy- 2l-acyloxy-pregnadiene compounds obtained in accordance with the foregoing dehydrohalogenation rocedures include 9-halo-A -3,11,20-triketo 17 hydroxy-Zl-acyloxy-pregnadiene compounds as for example 9ot-chloro- A -3,1l,20-triketo 17a hydroxy 21 acyloxy-pregnadienes such as 9a-chl0ro-A -3J1,20-triketo-l7ot,21-dihydroxy-pregnadiene 21-acetate, 9a-chloro-A -3J1,20-triketo ;,21 dihydroxy-pregnadiene 21-propionate, 9afluoro A -3,11,20 triketo 17oz hydroxy 21-acyloxypregnadienes such as 9Ot-fluOlO-A -3,11,2O-tl'lk6tO-l70t, 2l-dihydroxy-pregnadiene 21-acetate, 9a-fluoro-A -3J1, 20-triketo-1'7u,2l-dihydroxy-pregnadiene 21 propionate, 9u-fluoro-A -3,11,20-triketo 1711,21 dihydroxy pregnadiene 21-(tertiary butyl-acetate), 9OL-fiuOIO-A -3,11, 20-triketo-17u,2l-dihydroxy-pregnadiene 21 phosphate, 9-haloA -3,2O-diketo 11,17 dihydroxy 21 acyloxypregnadiene compounds as for example 9a-chloro-A -3, ZO-diketo 115,17 dihydroxy-Zl-acyloxy-pregnadienes such as 9Ot-Cl11OIO-A 3,ZQ-dlkBiO-llfi,17cc,21-tlll1ydI'OXypregnadiene 21 -acetate, 9a-chloro-A -3,ZO-diketo-l1B, 17u,21-trihydroxy-pregnadiene 21-propionate, 9a-fluoro- A -3,20-diketo 115,170; dihydroxy-Zl-acyloxy-pregnadienes such as 9a-fiuoro-3,20-diketo-11B,17a,21-trihydroxy-pregnadiene ,21 acetate, 9OL-flHOl'O-3,20-dlk6t0-11B, 17,2l-trihydroxy-pregnadiene 21-propionate, 9OL-fi1101'0- 3,20-diketo 11fl,17oc,21 trihydroxy-pregnadiene 2l-(tertiary butyl-acetate), 9a-fluoro-3,20-diketo-11fi,17u,21-trihydroxy-pregnadiene 21-phosphate.

The 9-halo-A -3,20-diketo-1l-oxygenated -'17-hydroxy- 21-acyloxy-pregnadiene compound may then be reacted with a hydrolyzing agent as for example a solution of an alkali metal hydroxide such as potassium hydroxide in a lower alkanol, such as ethanol or methanol, to form the corresponding 9-halo-A -3,20-diketo-1l-oxygenated- 17,2l-dihydroxy-pregnadiene compound. This hydrolysis is preferably conducted by dissolving the 9-halo-A 3,20-diketo-1 1oxygenated-17-hydroxy-21-acyloxy-pregnadiene compound in a mixture of benzene and methanolic potassium hydroxide, and allowing the resulting solution to stand at room temperature for a period of about ten minutes; at the end of this hydrolysis period, the solution is acidified with acetic acid, and the benzene is evaporated in vacuo to give the corresponding 9-halo- A 3,20-diketo-1l-oxygenated-17,21-dihydroxy-pregnadiene compound. The 9-ha1o-A -3,20-diketo-1l-oxygenated 17,21 dihydroxy pregnadiene compounds obtained in accordance with this hydrolysis procedure include 9-halo-A -3,l1,20 triketo-17,2l-dihydroxy-pregnadienes such as 9oc-Ch1O1O-A 3,11,20-l1'ikBl1Ol7ot,21-dlhydroxy-pregnadiene, 90c fluoro-A -3,11,20-triketo-17u,- 2l-dihydroxy-pregnadiene, 9 halo-A -3,20-diketo-11,17- 21-tri hydroxy-pregnadienes such as 9a-chloro-A -3,20- Clik6t0-11B,17u,21 trihydroxy-pregnadiene, 90 fluoro- A -3,ZQ-dll iO11,8,17a,21 trihydroxy-pregnadiene, and the like.

The 9-halo-A -3 ,1 1,20-triketo-17,21-dihydroxy-pregnadienes and 9 -halo-A -3,20-diketo-11,17,21-trihydroxypregnadienes thus obtained can be reacted, if desired, with an acylating agent as for example a lower alkanoic anhydride such as acetic anhydride, propionic anhydride,

tertiary butyl-acetyl chloride, and the like, in the presence of a tertiary amine such as pyridine thereby producing the corresponding 9-halo-A -3,11,20-triketo-l7- hydroxy-Zl-alkanoyloxy-pregnadiene and 9-halo-A -3,20- diketo-l 1,17-dihydroxy-21-alkanoyloxy-pregnadiene.

The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given for purposes of illustration and not of limitation.

Example I 202 mg. of 9a-fluoro-3,11,ZO-triketo-17u-hydroxy-21- acetoxy-allopregnane is dissolved in 15 cc. of chloroform, and to the resulting mixture is added dropwise 4.3 cc. of a 0.0011 N chloroform solution of bromine in 10 cc. of chloroform. This solution is allowed to stand at room temperature for about hours, and the chloroform solution evaporated to dryness in vacuo to give 2,4 dibromo-9a-fluoro-3,11,20-triketo-17a-hydroxy- 21-acetoxy-allopregnane.

This 2,4-dibromo compound is dissolved, Without purification, in 25 cc. of glacial acetic acid and to the solution is added 282 mg. of 2,4-dinitrophenylhydrazine. The resulting solution is heated under nitrogen at 50-55 C. for two hours, and the reaction solution is Worked up in the conventional manner to give the desired A -3,11,20- triketo-l7a-hydroxy-2l-acetoxy-pregnadiene 3 (2,4 dinitrophenylhydrazone). This crude hydrazone is mixed with 17.5 cc. of 90% aqueous pyruvic acid and 3.5 cc. of glacial acetic acid, and the mixture is heated under nitrogen, with agitation, at a temperature of about 80*85 C. for a period of approximately five and onehalf hours. (A clear solution is obtained after heating the mixture for a period of approximately 45 minutes.) The reaction solution is evaporated in vacuo to a small volume, and the residual solution is diluted with a large quantity of chloroform. The solid material which precipitates is removed by filtration, and the chloroform filtrate is extracted with two portions of Water, with three portions of dilute aqueous potassium bicarbonate solution, and finally with another portion of water. Evaporation of this washed chloroform solution to dryness gives A -9a fiuoro-3,11,20-triketo-17a,21-dihydroxy pregnadiene. This material is reacted with acetic anhydride and pyridine to give A 9oc-flllOI'O-3,l1,20-111'lk6t0-l7ahydroxy-Zl-acetoxy-pregnadiene (sometimes referred to herein as 9u-fluoro-retrocortin 21-acetate).

The 9oc-fluor0-3,11,2O-triketo-17u-hydroxy-21-acetoxyallopregnane used as starting material in this example may be prepared starting with 9oc-fll1010 cortisone acetate (13 -90: fluoro-3,l1,20-triketo-17a-hydroxy-21-acetoxy-pregnene) as follows: 600 mg. of palladium oxide are added to a suspension of 7.25 g. of said A -9a-fiuoro- 3,11,20 -.triketo-l7ot-hydroxy-2l-acetoxy-pregnene in 600 cc. of methanol, and the mixture is reacted with hydrogen at a pressure of about 40 pounds per square inch while maintaining the reactants at about room temperature. The absorption of hydrogen ceases after about one-half hour; the amount of hydrogen absorbed corresponds to one mole. The reaction mixture is filtered, thereby removing the catalyst, and the catalyst is Washed thoroughly with chloroform. A few drops of ethanolic hydrogen chloride are added to the combined filtrate and washlugs, and the resulting solution is evaporated to dryness in vacuo. The residual material is dissolved in chloroform, and the solution is again evaporated to dryness. The residual material is then recrystallized twice from acetone to give about 6 grams of substantially pure 9afiuoro 3,11,20 triketo-17a-hydroxy-2l-acetoxy-allopregnane (sometimes referred to herein as 906-fillOI'O-I'Ctl'0- cortane 21-acetate).

Example 2 Similarly, 9a-fluoro-hydrocortisone acetate is hydrogenated to give 9a-fiuoro-3,20-diketo-11B,17m-dihydroxy- Zl-acetoxy-allopregnane which, upon reaction with bromine in accordance with the foregoing procedure, is converted to 2,4-dibromo-9a-fluoro-3,ZO-diketo-11,8,17a-dihydroxy-Zl-acetoxy-allopregnane. The latter is then reacted with 2,4-dinitrophenylhydrazine and the intermediate 2,4 dinitrophenyl -hydrazone is hydrolyzed in the presence of pyruvic acid to give A -9Ot-fiuO1'0'3,20-diketo-l1B,17a,2l-trihydroxy-pregnadiene. This material is reacted with acetic anhydride and pyridine in accordance with the conventional method to give A -9oc-fi1101'O3,20- diketo-l 1,8,17ot-dihydroxy-2l-acetoxy-pregnadiene (sometimes referred to herein as 9a-fiuoro-hydro-retrocortin 21- acetate).

The details'of the procedure outlined hereinabove are as follows: 202 mg. of 9a-fl'l10lO-3,20-dik6tO-11fi,l70c-di hydroxy-2l-acetoxy-allopregnane is dissolved in 15 cc. of

chloroform, andto the resulting mixture is added dropwise 4.3 cc. of a 0.0011 N chloroform solution of bromine in 10 cc. of chloroform. This solution is allowed to stand at room temperature for about fifteen hours, and the chloroform solution evaporated to dryness in vacuo to give 2,4-dibromo-9a-fluoro-3,20-diketo-11,8,17m-dihydroxy-2l-acetoxy-allopregnane.

This 2,4-dibromo compound is dissolved, without purification, in 25 cc. of glacial acetic acid and to the solution is added 282 mg. of 2,4-dinitrophenylhydrazine. The resulting solution is heated under nitrogen at 50-55 C. for two hours, and the reaction solution is Worked up in the conventional manner to give the desired A -3,20- d-iketo-l 113, 17 a-dihydroxy-2 l-acetoxy-pregnadiene 3- (2,4- dinitrophenylhydrazone). This crude hydrazone is mixed with 17.5 cc. of 90% aqueous pyruvic acid and 3.5 cc. of glacial acetic acid, and the mixture is heated under nitrogen, with agitation, at a temperature of about C. for a period of approximately five and one-half hours. (A clear solution is obtained after heating the mixture for a period of approximately forty-five minutes.) The reaction solution is evaporated in vacuo to a small volume, and the residual solution is diluted with a large quantity of chloroform. The solid material which precipitates is removed by filtration, and the chloroform filtrate is extracted with two portions of water, with three portions of dilute aqueous potassium bicarbonate solution, and finally with another portion of water. Evaporation of this washed chloroform solution to dryness gives A 9oc-fiI1O103,20'- diketo 11,8, 17a,21-trihydro-xypregnadiene. This material is reacted with acetic anhydride and pyridine to give A -9a-fluoro-3,ZO-diketo-l1,8, 17a-dihydroxy-21-acetoxy-pregnadiene.

, The 9oc-flUOIO-3,20-dik6t0 115,17a dihydroxy-Zl-acetoxy-allopregnane used as starting material in this example may be prepared starting with 9a-fluoro-hydrocortisone acetate (A -9u-fluoro-3,20-diketo-11,8,l7u dihydroxy-Z 1- acetoxy-pregnane) as follows: 600 mg. of palladium oxide are added to a suspension of 7.25 g. of said A -9afluoro-3,20-diketo-115,17a-dihydroxy 21 acetoxy pregnane in 600 cc. of methanol. The mixture is reacted with hydrogen at a pressure of about 40 pounds per square inch while maintaining the reactants at about room temperature. The absorption of hydrogen ceases after about one-half hour; the amount of hydrogen absorbed corresponds to one mole. The reaction mixture is filtered, thereby removing the catalyst, and the catalyst is Washed thoroughly with chloroform. A few drops of ethanolic hydrogen chloride are added to the combined filtrate and washings, and the resulting solution is evaporated to dryness in vacuo. The residual material is dissolved in chloroform, and the solution is again evaporated to dryness. The residual material is then recrystallized twice from acetone to give about 6 grams of substantially pure 9u-flll0IO-3,20-dik$lZO-l15,17zz-dihyd1'0XY-21 acetoxy-allopregnane (sometimes referred to herein as 9a-fiuorohydro-retrocortane 21-acetate) Example 3 One gram of 9a-fluoro-3,20-diketo-11B,17a-dihydroxy- 2l-acetoxy-allopregnane is dissolved in 35 cc. of glacial acetic acid, and to this solution is added five drops of an 0.95 N solution of hydrogen bromide in glacial acetic acid. To this solution is added a glacial acetic acid solution containing two molecular equivalents of bromine (based on the steroid compound) and, after the uptake of bromine is complete, an additional 6 cc. of the 0.95 N solution of hydrogen bromide in glacial acetic acid is added. The resulting solution is maintained at room temperature for a period of approximately two and one-half hours. The reaction mixture is poured into water, and the precipitated material is recovered by filtration and dried to give 2,4-dibromo-9a-fluoro-3,20-diketo-1113,170:- dihydroxy-2l-acetoxy-allopregnane.

The 2,4-dibromo-9a-fluoro-3,20 diketo 11 B,17oa-dihydroxy-2l-acetoxy-allopregnane. thus obtained is mixed with 2 cc. of collidine and cc. of dimethylformamide and the mixture is heated under reflux for a period of about 100 minutes. The reaction mixture is cooled and distributed between dichloromethane and dilute aqueous hydrochloric acid solution. The dichloromethane layer is washed with dilute aqueous hydrochloric acid solution and then with water until neutral and free of dimethylformamide. The solvent is evaporated from the washed dichloromethane layer in vacuo, and the residual material is purified chromatographically to give substantially pure A -9a-flu0r0 3,20 diketo 1118,1711 dihydroxy-Zl-acetoxy-pregnadiene; M.P. 237 C.; [u] +lOO.9 in acetone; ultraviolet absorption spectrum: A max. in methanol=239 m (log E 4.19); max. in sulfuric acid-310 ma (log E 4.06) and 262.5 my (log E 4.18); infrared absorption spectrum: 7\. max.=2.92,u, 3.02g, 5.74g, 5.82m, 6.0a, 6.12 s, 621a, 1118a.

Example 4 Eight grams of 2,4-dibromo-9a-fiuoro-3,ZO-diketo-11B, 17a-dihydroxy-2l-acetoxy-allopregnane is mixed with 18 cc. of collidine and 45 cc. of dimethylformamide, and the mixture is heated under reflux for a period of about 100 minutes. The reaction mixture is cooled and distributed between chloroform and 2.5 N aqueous hydrochloric acid solution. The chloroform layer is washed with dilute aqueous hydrochloric acid solution, with 5% aqueous sodium bicarbonate solution, and then with water until neutral until free of dimethylformamide. The solvent is evaporated from the washed chloroform layer in vacuo to give 6.19 g. of crude A -9a-fluoro-3,20-diketo-l16,170:- dihydroxy-2l-acetoxy-pregnadiene. 6.15 g. of this crude A -9u-fluoro 3,20 diketo 11,8,17a dihydroxy-21-acetoxy-pregnadiene is dissolved in 135 cc. of 2:1 benzene: chloroform mixture, and the resulting solution passed through a column of 258 g. of neutral alumina. The resulting adsorbate is eluted with chloroform, the chloroform eluate is evaporated to dryness in vacuo, and the residual material is recrystallized from acetone to give substantially pure A -9a-fluoro-3,ZO-diketo-1113,170:- dihydroxy 21 acetoxy pregnadiene; M.P. 236 C.; [u] 100.9 in acetone; ultra-violet absorption spectrum: A max. in methanol=239 mg (6 15,400), A max. in sulfuric acid=310 111,11. (E 10,400) and 263 m (e 13,300). Anal. calcd. for C H O F: C, 65.70; H, 6.95; found: C, 65.66; H, 6.74.

The 2,4-d-ibromo 9oz fiuoro-3,20-diketo-11B,17a-dihydroxy-2l-acetoxy-allopregnane starting material may be prepared as follows: 6.0 g. of 5% palladium on charcoal catalyst are added to a suspension of 7.25 g. of 13 fluoro 3,20 diketo l1 S,17u,2l-trihydroxy-pregnene 21- acetate in 750 cc. of methanol, and the mixture is reacted with hydrogen at atmospheric pressure while maintaining the reactants at about room temperature. The absorption of hydrogen ceases after about 15 minutes; the amount of hydrogen absorbed corresponds to one mole. The reaction mixture is filtered, thereby removing the catalyst, and the catalyst is washed thoroughly with methanol. The combined filtrate and washings are evaporated to dryness, and the residual material is recrystallized from acetone to give about 4 g. of 90t-fl1101O-3,20-dlk8l0-11B,].7oc-dlhY- droxy-Zl-acetoxy-allopregnane. One gram of this 90cfluoro-3,20-dilreto-l1fi,l7u-dihyd.roxy 21 acetoxy allopregnane is dissolved in 35 cc. of glacial acetic acid, and to this solution is added a few drops of a one normal glacial acetic acid solution of hydrogen bromide. To this solution is added a glacial acetic acid solution containing two molar equivalents of bromine; after the absorption of bromine is complete, about 6 cc. of an approximately 1 N solution of HBr in acetic acid is added, and the solution is held at about 20 C. for 2 /2 hours. The reaction mixture is poured into water, and the precipitated material is recovered by filtration and dried to give 2,4- dibromo 9oz fluoro-3,20 diketo-1 1fi,l7a-dihydroxy-2 1- acetoxy-allopregnane.

Example 5 0.5 g. of A -9a-fiuoro-3,ZO-diketo-1113,17a-dihydroxy- 21-acetoxy-pregnadiene is dissolved in a mixture of 5 cc. of benzene and 5 cc. of 1.1 N methanolic potassium hydroxide, and the solution is allowed to stand at room temperature for a period of about ten minutes. The resulting solution is acidified with acetic acid, the benzene is evaporated in vacuo, and the residual material is recrystallized from ethyl acetate to give substantially pure diene (sometimes referred to herein as 9u-fluoro-hydroretrocortin) Example 6 One gram of 9u-fluoro-3,11,20-triketo-17a-hydroxy-21- acetoxy-allopregnane is dissolved in 35 cc. of glacial acetic acid, and to this solution is added five drops of an 0.95 N solution of hydrogen bromide in glacial acetic acid. To this solution is added a glacial acetic acid solution containing two molecular equivalents of bromine (based on the steroid compound) and, after the uptake of bromine is complete, an additional 6 cc. of the 0.95 N solution of hydrogen bromide in glacial acetic acid is added. The resulting solution is maintained at room temperature for a period of approximately 2 /2 hours. The reaction mixture is poured into water, and the precipitated material is recovered by filtration and dried to give 2,4 dibromo-9a-fluoro-3,11,20-triketo-17a-hydroxy- 21-acetoxy-allopregnane.

The 2,4-dibromo-9a-fiuoro-3, 1 1,20-triketo-17a-hydroxy- 21-acetoxy-allopregnane thus obtained is mixed with 2 cc. of collidine and cc. of dimethyl-formamide and the mixture is heated under reflux for a period of about 100 minutes. The reaction mixture is cooled and distributed between dichloromethane and dilute aqueous hydrochloric acid solution. The dichloromethane layer is washed with dilute aqueous hydrochloric acid solution and then with water until neutral and free of dimethyl formamide. The solvent is evaporated from the washed dichloromethane layer in vacuo, and the residual material is purified chromatographically to give substantially pure A -9wfl110f0- 3,1 1,20-triltetol7a-hydroxy-2 l-acetoxy-pregnadiene.

0.5 g. of A -9u-fiuoro-3,11,ZO-triketo-17a-hydroxy21- acetoxy-pregnadiene is dissolved in a mixture of 5 cc. of benzene and 5 cc. of 1.1 N methanolic potassium hydroxids, and the solution is allowed to stand at room temperature for a period of about ten minutes. The resulting solution is acidified with acetic acid, the benzene is evaporated in vacuo, and the residual material is recrystallized from ethyl acetate to give substantially pure A -9wfluoro- 3,11,ZO-triketo-17a,2l-dihydroxy-pregnadiene (sometimes referred to herein as 9a-fluoro-retrocortin).

Example 7 Fifty parts of reagent glacial acetic acid are added to a solution of 0.5 part of 9a-fluoro-3,l1,20-triketo-17a,21- dihydroxy-allopregnane 2l-phosphate (sometimes referred to herein as 9u-fluoro-retrocortane 2l-phosphate) in 5 parts of chloroform. A few drops of a 0.1 N solution of hydrogen bromide in acetic acid is added, and the resulting solution is stirred while adding thereto, dropwise at room temperature, a solution containing two molecular equivalents of bromine (based on the 9a-fiuoro-retrocortane 2l-phosphate) dissolved in tWo parts of glacial acetic acid. The reaction solution is evaporated to dryness in vacuo, and the residual material is triturated with low boiling petroleum ether, and the insoluble material is recovered and dried to give approximately 0.4 part of 2,4- ClibIOHlO-9cc-fill0lO-3,l 1,20-triketo-17m,21 dihydroxy-allopregnane 2l-phosphate (sometimes referred to herein as 2,4-dibromo-9e-fiuoro-retrocortane 2 lphosphate) 0.5 part of 2,4 dibromo 90c fluoro retrocortane ZI-phosphate is heated under reflux with parts of collidine for one hour; the reaction mixture is concentrated to dryness in vacuo, the residue dissolved in water and the solution then passed through a column containing 200 parts of a strongly acidic ion-exchange resin. The resultant solution is lyophilized to give 9u-fluoro-A -3J1, 20 triketo 1711,21 dihydroxy-pregnadiene ZI phosphate (sometimes referred to herein as 9a-fluoro-retrocortin 2 l-phosphote) The 9a fluoro 3,11,20 triketo 17a,2-1 dihydroxyallopregn-ane 21-phosphate used as starting material in this example may be prepared as follows: 600 mg. of palladium oxide are added to a suspension of 7.25 g. of A 3,11,20 triketo 17oz hydroxy 21 acetoxypregnene in 600 cc. of methanol. The mixture is reacted with hydrogen at a pressure of about 40 pounds per square inch while maintaining the reactants at about room temperature. The absorption of hydrogen ceases after about one-half hour; the amount of hydrogen absorbed corresponds to one mole. The reaction mixture is filtered, thereby removing the catalyst, and the catalyst is Washed thoroughly with chloroform. A few drops of ethanolic hydrogen chloride are added to the combined filtrate and washings, and the resulting solution is evaporated to dryness in vacuo. The residual material is dissolved in chloroform, and the solution is again evaporated to dryness. The residual material is then recrystallized twice from actone to give about 6 grams of substantially .pure 90c fluoro 3,11,20 triketo 17a hydroxy 21 acetoxyallopregnane (sometimes referred to herein as 9u-fl-u0roretrocortane Z'I-acetate) 5 grams of 9oz fiuoro retrocortane 21 acetate are dissolved in :a mixture of 50 cc. of benzene and 50 cc.

of 1.1 N mc-thanolic potassium hydroxide, and the solution is allowed to stand at room temperature for a period of about 10 minutes. The solution is then acidified with acetic acid, the benzene is evaporated in vacuo, and the residual material is recrystallized from ethyl acetate to give substantially pure 9oz fluoro 3,11,2 0 triketo-l7a, ZI-dihydroxy-al-lopregnane (sometimes referred to herein as 9a-flIlOP0-ICFOCOI-t-8.I16)

A mixture of 2 parts of a -fiuoro retrocortane and hour parts of the dioxolane of mesityl oxide in 15 parts of dry tetrahydrofuran is treated with 0.13 part of concentrated sulfuric acid and stirred at room temperature for about two hours. The mixture is then cooled to 0 C. and allowed to stand for approximately 16 hours. Pyridine is added to neutralize the acid and the product is precipitated by the addition of petroleum ether. The precipitated material is recovered by filtration and recrystallized from ethanol to give substantially pure 9a fluoro- 3,11,20 triketo 170:,21 dihydroxy allopregnane 3- e-thylene cyclic ketal (sometimes referred to herein as 90:- fluoro retrocontane 3 ethylene cyclic ketal).

A mixture of 3.5 parts of 90a fluoro retrocortane 3- ethylene cyclic ket-al in 24 parts of pyridine is cooled to 0 C. To the cooled mixture is added 14 parts of methane sulfonyl chloride, and the resulting mixture maintained at 0 C. for three hours. The reaction mixture is then poured into ice water whereupon the product separates as a solid, which is recovered by filtration, dried and recrystallized from acetone to give substantially pure 9oz fiuoro 3,11,20 triketo 17cc,21 dihydroxy-allopregnane 3-ethylene cyclic ketal ZI-methane sulfonate (sometimes referred to herein as 904 fiuoro retrocortane 3-ethylene cyclic ket-al ZI-methane sulfonate).

A mixture of 1.5 parts of 9a fluoro retrocortane 3- ethylene cyclic ketal ZI-methane sulfonate, 1.1 parts of sodium iodide and parts of ethanol are heated under reflux for approximately 30 minutes. The entire reaction mixture is filtered, and the filtered solution is evaporated in vacuo to about 100 parts. To this concentrated solution are added 100 parts of water, and the aqueous mixture thus obtained is evaporated to give approximately parts of an aqueous suspension. This suspension is filtered, and the solid material is washed with water and dried to give 21 iodo 90 fiuoro 3,11,20 triketo- 1701,21 dihyd-roxy allopregnane 3 ethylene cyclic ket-al (sometimes referred to herein as 21 iodo 90a fluororetroc-ortane 3-ethylene cyclic ketal) Approximately 0.75 part of 21 iodo 90c fluoro-retrocontane 3-ethylene cyclic ketal and 0.6 part of silver dibenzyl phosphate are suspended in 150 parts of henzene, and water is removed by evaporating the mixture to a volume of 75 parts. The resulting, concentrated benzene mixture is heated under reflux for about 1 6 hours, and filtered while hot to separate the silver iodide from the benzene solution. The filtered benzene solution is evaporated to a heavy syrup, and is then redissolved in a mmamum quantity of benzene-about 4 parts. The resulting benzene solution is then diluted with petroleum ether to effect crystallization of the material which is recovered by filtration and dried to give 90; fluoro 3,11, 20 triketo 1701,21 dihydroxy allopregnane S-ethylene cyclic ketal 21-dibenzyl phosphate (sometimes referred to herein as 911 fiuoro retroc-ortane 3-ethylene cyclic ketal 21-dibenzyl phosphate).

A solution of 0.5 part of 91x fiuoro retrocortane 3- ethylene cyclic ketal 21-dibenzyl phosphate in 100 parts of ethanol containing two parts of N-methyl morpholine is hydrogenated at 25 C. at atmospheric pressure in the presence of about 0.5 part of pre-reduced palladium oxide catalyst. When hydrogenation is complete, as determined by the quantity of hydrogen (2 moles) taken up, the reaction mixture is filtered to remove thecatalyst, and the filtrate, which contains the N-methyl-morpholine salt of 9a fluoro retrocor'tane 3-ethylene cyclic ketal 21- phosphate, is evaporated in vacuo to a syrupy residue.

The syrup is dissolved in water, and the aqueous solution is washed with ethyl acetate and ether to remove impurities insoluble in these organic solvents. The aqueous solution is then evaporated to dryness to give the N- me-thyl morpholine salt of 9a fluoro 3,11,20 triketo- 1:7u,21-dihydroxy allopregnane 3-ethylene cyclic ketal 21- phosphate (sometimes referred to herein as 90: fluororetrocortane 3-ethylene cyclic ketal Zl-phosphate).

The 9a-fiuoro-retrocortane S-ethylene cyclic ketal 21- phosphate is dissolved in acetone containing a small amount of dilute aqueous hydrochloric acid, and the resulting solution is heated under reflux for about 15 minutes. The reaction solution is evaporated in vacuo to give 9a fluoro-3,l1,20-triketo-1704,21-dihydroxyallopregnane 21-ph0sphate (sometimes referred to herein as 90:- fluoro-retrocortane 21-phosphate Example 8 Fifty parts of reagent glacial acetic acid are added to a solution of 0.5 part of 9m-fluoro-3,20-diketo-l lfi,l7a,2ltrihydroxy allopregnane 21-phosphate (sometimes referred to herein as 9ot-iluoro-hydroretrocortane 21-phosphate) in parts of chloroform. A few drops of a 0.1 N solution of hydrogen bromide in acetic acid is added, and the resulting solution is stirred while adding thereto, dropwise, at room :temperature, a solution containing two molecular equivalents of bromine (based on the 9u-fluorohydroretrocortane 21-phosphate) dissolved in two parts of glacial acetic acid. The reaction solution is evaporated to dryness in vacuo, and the residual material is triturated with low-boiling petroleum ether, and the insoluble material is recovered and dried to give approximately 0.4 part of 2,4-dibromo-9a-fluoro-3,ZO-diketo-l1fi,17u,21-trihydroxy-allopregnane 21-phosphate (sometimes referred to herein as 2,4-dibromo-9ot-fluoro-hydro-retrocortane 21:

' phosphate).

0.5 part of 2,4-dibromo-9wliuoro-hydro-retrocortane 21-phosphate is heated under reflux with 10 par-ts of collidine for one hour; the reaction mixture is concentrated to dryness in vacuo, the residue dissolved in water and the solution then passed through a column containing 200 parts of a strongly acidic ion exchange resin. The resultant solution is lyophilized to give 9a-fiuoro-A -3,20- diketo 11B,17,21 trihydroxypregnadiene 21 phosphate (sometimes referred to herein as 9ot-fluoro-hydro-retrocortin 2l-phosphate).

The 90: fluoro 3,20-diketo-llfl,17a,21-trihydroxyallopregnane 21-phosphate used as starting material in this example may be prepared as follows: 600 mg. of palladium oxide are added to a suspension of 7.25 g. of 13 -3 ,20- diketo-llfl,l7ot-dil1ydroxy-21-acetoxy-pregnene in 600 cc. of methanol. The mixture is reacted with hydrogen at a pressure of about 40 pounds per square inch while maintaining the reactants at about room temperature. The absorption of hydrogen ceases after about one-half hour; the amount of hydrogen absorbed corresponds to one mole. The reaction mixture is filtered, thereby remov ing the catalyst, and the catalyst is washed thoroughly with chloroform. A few drops of ethanolic hydrogen chloride are added to the combined filtrate and washings, and the resulting solution is evaporated to dryness in vacuo. The residual material is dissolved in chloroform, and the solution is again evaporated to dryness. 'The residual material is then recrystallized from acetone to give about 6 grams of substantially pure 9a-fluoro-3,20-diketo-l 15,17u-dihydroxy-21-acetoxy-allopregnane (sometimes referred to herein as 9a-fluoro hydro-retrocortane 21-acetate).

Five grams of 9e-fiuoro-hydro-retrocortane 21-acetate are dissolved in a mixture of 50 cc. of benzene and 50 cc. of 1.1 -N methanolic potassium hydroxide, and the solution is allowed to stand at room temperature for a period of about 10 minutes. The solution is then acidified with acetic acid, the benzene is evaporated in vacuo, and the residual material is recrystallized from ethyl acetate to 12 give substantially pure 9oc-fiu0lO-3,20dlkctO-1lfi,l7oz,2ltrihydroxy allopregnane (sometimes referred to herein as 9ot-fluoro-hydro-retrocortane) A mixture of two parts of 9a-fluoro-hydro-retrocortane and four parts of the dioxylane of mesityloxide in 15 parts of dry tetrahydrofuran is treated with 0.13 part of concentrated sulfuric acid and stirred for about two hours. The mixture is then cooled to 0 C. and allowed to stand for approximately 16 hours. Pyridine is added to neutralize the acid and the product is precipitated by the addition of petroleum ether. The precipitated material is recovered by filtration and recrystallized from ethanol to give substantially pure 9ot-fluoro-3,20-diketo-1113,17a, 21-trihydroxy-allopregnane-3-ethylene cyclic ketal (sometimes referred to herein as 9u-fluoro-hydro-retrocortane 3-ethylene cyclic ketal).

A mixture of 3.5 parts of 9a-iluoro-hydro-retrocortane 3-ethylene cyclic keta-l in 24 pants of pyridine is cooled to 0 C. To the cooled mixture is added 14 parts of methane sulfonyl chloride, and the resulting mixture is maintained at 0 C. for 3 hours. The reaction mixture is then poured into ice water and the solid material which precipitmes is recovered by filtration, dried and recrystallized from acetone to give substantially pure 9ot-fluoro 3,20-diketo-1 lfi,17a,2l-trihydroxy-allopregnane 3-ethylene cyclic ketal ZI-methane sulfonate (sometimes referred to herein as 9ot-fluoro-hydro-retrocortane 3-ethylene cyclic ketal ZI-methane sulfonate).

A mixture of 1.5 parts of 9a-fluoro-hydro-retrocortane S-e-thylene cyclic ketal 21-methane sulfonate, 1.1 parts of sodium iodide and 140 parts of ethanol are heated under reflux for approximately 30 minutes. The entire reaction mixture is filtered, and the filtered solution is evaporated in vacuo to about 100 parts. To this concentrated solution are added 100 parts of water, and the aqueous mixture thus obtained is evaporated to give approximately 150 parts of an aqueous suspension. This suspension is filtered, and the solid material is washed with Water and dried to give 21-iodo-9a-fluoro-3,20-diketo-llfl,170:,2l-trihydroxy-allopregnane 3-ethylene cyclic ketal (sometimes referred to herein as 21-iodo-9a-fluorohydro-retrocortane 3-ethylene cyclic ketal).

Approximately 0.75 part of 2l-iodo-9a-fiuoro-hydroretrocortane 3-ethylene cyclic ketal and 0.6 part of silver dibenzylphosphate are suspended in 150 parts of benzene, and water is removed by evaporating the mixture to a volume of 75 parts. The resulting, concentrated benzene mixture is heated under reflux for about 16 hours, and filtered while hot to separate the silver iodide from the benzene solution. The filtered benzene solution is evaporated to a heavy syrup, and is then redissolved in a minimum quantity of benzene. The resulting benzene solution is diluted with petroleum ether, and the material which crystallizes from the solution is recovered by filtration and dried to give t-fluOIO-3,20-dlk6tO-11,3,170t,21- trihydroxy-allopregnane 3-ethylene cyclic ketal Z-dibenzylphosphate (sometimes referred to herein as 9oc-fitl010- hydro-retrocortane 3-ethylene cyclic ketal 21-dibenzylphosphate).

A solution of 0.5 part of 9a-fluoro-hydroretrocortane 3- ethylene cyclic ketal 2l-dibenzylphosphate in parts of ethanol containing 2 parts of N-methylmorpholine is hydrogenated at 25 C. at atmospheric pressure in the presence of about 0.5 part of prereduced palladium oxide catalyst. When hydrogenation is complete, i.e. after 2 moles of hydrogen have been absorbed, the reaction mixture is filtered to remove the catalyst, and the filtrate, which contains the N-methyl-morpholine salt of 9oc-flll01'0- hydro-retrocortane S-ethylene cyclic ketal 21-phosphate, is evaporated in vacuo to a syrupy residue. The syrup is dissolved in water, and the aqueous solution is washed with ethyl acetate and ether to remove impurities insoluble in these organic solvents. The aqueous solution is then evaporated to dryness to give the N-methylmorpholine salt of 9a-fluoro-3,20-diketo-11B,17a,21-tri 13 hydroxy-allopregnane 3-ethylene cyclic ketal 2l-phosphate (sometimes referred to herein as 9u-fiuoro-hydro-retrocortane 3-ethylene cyclic ketal 2l-phosphate) The 9u-fluoro-hydro-retrocortane 3-ethylene cyclic ketal 21-phosphate is dissolved in acetone containing a small amount of dilute aqueous hydrochloric acid, and the resulting solution is heated under reflux for about 15 minutes. The reaction solution is evaporated in vacuo to give 9a-fluoro-3,20-diketo-11,3,17u,21-trihydroxy-allopregnane 21-phosphate (sometimes referred to herein as 9a-fiuoro-retrocortane 21-phosphate).

Example 9 A solution of about 4 parts of tertiary butyl-acetyl chloride in 17 parts of dry chloroform is added portionwise to a cold solution of 10 parts of 9a-fluoro-hydro-retrocortin (which may be prepared as described in Example 3 hereinabove, and which has the chemical name A -9afluoro-3,2O-diketo-1113,170:,21-trihydroxy-pregnadiene) in 50 parts of anhydrous pyridine. The resulting solution is allowed to stand at to 5 C. for about 15 hours, and the reaction solution is poured into 300 parts of Water. The resulting aqueous mixture is extracted with four portions of chloroform each containing approximately 100 parts. The combined chloroform layers are washed with water, dilute aqueous hydrochloric acid solution, water, 5% aqueous sodium bicarbonate solution, and finally with water. The chloroform extract is dried over magnesium sulfate, and the chloroform is evaporated in vacuo to give a residual oil, which is triturated with alcohol until it crystallizes. This material is recrystallized from ethanol to give substantially pure A -9u-fi11O1O 3,20-diketo-1 1B,17u,2l-trihydroxy-pregnadiene 21- (tertiary butyl-acetate), sometimes referred to herein as 9afluoro-hydro-retrocortin 21-tertiary butyl-acetate.

Example 10 A solution of about 4 parts of tertiary butyl acetyl chloride in 17 parts of dry chloroform is added portionwise to a cold solution of 10 parts of 9on-fluOIO-16tlOCOItiI1 (which may be prepared as described in Example 4 hereinabove, and which has the systematic chemical name A 9a-fiuoro-3,11,20-triketo-l7a,2l-dihydroxy-pregnadiene) in 50 parts of anhydrous pyridine. The resulting solution is allowed to stand at 0.25 C. for about 15 hours, and the reaction solution is poured into 300 parts of water. The resulting aqueous mixture is extracted with four portions of chloroform each containing approximately 100 parts. The combined chloroform layers are washed with water, dilute aqueous hydrochloric acid solution, water, 5% aqueous sodium bicarbonate solution, and finally with water. The chloroform extract is dried over magnesium sulfate, and the chloroform is evaporated in vacuo to give a residue which is crystallized from alcohol to give A -9m-fluoro-3,11,20-triketo-l7a,21-dihydroxy-pregnadiene 21-(tertiary butyl-acetate), sometimes referred to herein as 9u-fluoro-retrocortin ZI-tertiary butyl-acetate.

Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims, they are to be considered as part of my invention.

I claim:

1. 2,4 dibromo-9-halo-3,20-diketo-l1fi,17u-dihydroxy- 21-lower alkanoyloxy-allopregnane.

2. 2,4 dibromo-9a-chloro-3,20-diketo-115,17a-dihydroxy-21-lower alkanoyloxy-allopregnane.

3. 2,4 dibromo 9(X-ChlOI'O-3,20-diklIO-11B,17OL,21-trihydroxy-allopregnane 21-acetate.

4. 2,4 dibromo c fiuoro-3,20-diketo-11/3,17a-dihydroxy-Zl-lower alkanoyloxy-allopregnane.

5. 2,4 dibromo -9u-fluoro-3,20-diketo-11fl,17oc,21-trihydroxy-allopregnane 21-acetate.

6. 2,4 dibromo-9-l1alo-3,11,20-triketo-17a-hydroxy-21- lower alkanoyloxy-allopregnane.

7. 2,4 dibromo-9u-flu0ro-3,11,20-triekto-17a-hydroxy- 2l-lower alkanoyloxy-allopregnane.

8. 2,4 dibromo-9a-fluoro-3,11,20-triketo-17a,21-dihydroxy-allopregnaue ZI-acetate.

References Cited in the file of this patent OTHER REFERENCES Fieser and Fieser: Natural Products, Related to Phenanthrene, 3rd edition (1949), page 451. 

1. 2,4-DIBROMO-9-HALO-3,20-DIKETO-11B,17A-DIHYDROXY21-LOWER ALKANOLYLOXY-ALLOPREGNANE.
 6. 2,4-DIBROMO-9-HALO-3,11,20-TRIKETO-17A-HYDROXY-21LOWER ALKANOYLOXY-ALLOPREGNANE. 